Autosomal Dominant Leukodystrophy (ADLD) is a fatal, progressive adult-onset disease characterized by autonomic and motor dysfunction with widespread CNS demyelination. We have previously shown that ADLD is caused by duplications of the lamin b1 gene and that increased expression of lamin B1 underlies the disease process. In eukaryotic cells, lamin B1 is a major constituent of the nuclear lamina, a fibrous meshwork adjacent to the inner nuclear membrane. The nuclear lamina maintains the structural integrity of the nucleus and has roles in essential cellular processes including transcription, DNA replication, DNA repair, and epigenetic regulation. We have recently demonstrated that transgenic (TG) mice with oligodendrocyte specific over-expression of lamin B1 exhibit severe vacuolar demyelination of the spinal cord that result in age dependent degenerative phenotypes reminiscent of ADLD. TG spinal cords showed dramatic reductions in the expression of multiple genes responsible for lipid synthesis, including the critical lipogenic transcription factors, SREBP1 and 2. This was accompanied by global increases in the repressive histone marks H3K9me3 and H3K27me3 in spinal cord oligodendrocytes. As myelin is made up of ~70% lipids, defects of lipid synthesis can result in severe demyelination. Consistent with our gene expression data, we observed a significant reduction of myelin enriched lipids that were specific to the spinal cord white matter. Our results identify lipid synthesis defects as a major component of the demyelination caused by lamin B1 over-expression and suggests a novel link between lamin B1 and lipid metabolism. While lipid dysregulation provides a cogent framework for explaining the demyelination observed in the transgenic mice, the mechanisms linking lamin B1 over-expression and lipid synthesis in oligodendrocytes are unknown and this proposal aims at identifying these pathways. We will test the hypothesis that lamin B1 modulates repressive histone marks to down regulate expression of specific target genes and examine whether lamin B1 over expression in oligodendrocytes results in the dysregulation of specific pathways that may impact oligodendrocyte function. We will also determine how modulating lamin B1 levels impacts the disease phenotype. The experiments that we have proposed will elucidate mechanisms linking lamin B1 over-expression, lipid dysregulation and the demyelination phenotype, results that will be critical in the identification of therapeutic pathways for ADLD. In addition, they will also provide insights into the basic biology of oligodendrocyte function that may help in understanding other common demyelinating diseases such as Multiple Sclerosis.